Isonicotinamide orexin receptor antagonists

ABSTRACT

The present invention is directed to isonicotinamide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behaviour (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX 1 receptor and OX 2receptor as the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to isonicotinamide compounds which areantagonists of orexin receptors, and which are useful in the treatmentor prevention of neurological and psychiatric disorders and diseases inwhich orexin receptors are involved. The invention is also directed topharmaceutical compositions comprising these compounds and the use ofthese compounds and compositions in the prevention or treatment of suchdiseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A¹ is selected from the group consisting of phenyl, naphthyl andheteroaryl;A² is selected from the group consisting of phenyl, naphthyl andheteroaryl;A³ is selected from the group consisting of phenyl, naphthyl,C₃₋₆cycloalkyl, —NR¹⁰R¹¹ and heterocycle;R^(1a), R^(1b) and R^(1c) may be absent if the valency of A¹ does notpermit such substitution and are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is independently 0 or 1,        n is independently 0 or 1 (wherein if m is 0 or n is 0, a bond        is present) and where the alkyl is unsubstituted or substituted        with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹³,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹³,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹³,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹³,        -   (f) phenyl, which is unsubstituted or substituted with R¹³,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹³,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(2a), R^(2b) and R^(2c) may be absent if the valency of A²        does not permit such substitution and are independently selected        from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(3a), R^(3b) and R^(3c) may be absent if the valency of A³        does not permit such substitution and are independently selected        from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R⁴ and R⁵ are independently selected from hydrogen and        C₁₋₆alkyl, which is unsubstituted or substituted with one or        more substituents selected from R¹³, or R⁴ and R⁵ may be joined        together to form a C₃₋₆cycloalkyl with the carbon atom to which        they are attached, where the cycloalkyl is unsubstituted or        substituted with one or more substituents selected from R¹³;        R⁶ is hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl, which is        unsubstituted or substituted with one or more substituents        selected from R¹³;        R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heterocycle,    -   (10) —CO₂H, and    -   (11) —CN;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A¹, A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c),R^(3a), R^(3b), R^(3c) and R⁴ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein A¹, A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c),R^(3a), R^(3b) and R^(3c) are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein A², A³, R^(1a)R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein A², A³, R^(1a), R^(1b), R^(2a), R^(2b), R^(2c), R^(3a), R^(3b)and R^(3c) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaId:

wherein A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaId′:

wherein A², A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIe:

wherein A³, R^(1a)R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a), R^(3b)and R^(3c) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaIf:

wherein A³, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIg:

wherein A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIh:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(3c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaII:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a),R^(3b) and R^(1c) are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIj:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a)and R^(3b) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaIj′:

wherein A², R^(1a), R^(2a), R^(2b), R^(2c), R^(3a) and R^(3b) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIIc

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c), R^(3a)and R^(3b) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaII:

wherein A¹, A², R^(1a), R^(1b), R^(1e), R^(2a), R^(2b), R^(2e), R^(3a),and R^(3b) are defined herein; or a pharmaceutically acceptable saltthereof.

An embodiment of the present invention includes compounds of the formulaIm:

wherein A¹, A², R^(1a), R^(1b), R^(1c), R^(2a), R^(2b) and R^(2e) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIn:

wherein A¹, A², R^(1a)R^(1b), R^(1c), R^(2a), R^(2b) and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A¹ isphenyl. An embodiment of the present invention includes compoundswherein A¹ is naphthyl. An embodiment of the present invention includescompounds wherein A¹ is heteroaryl. An embodiment of the presentinvention includes compounds wherein A¹ is pyridyl.

An embodiment of the present invention includes compounds wherein A² isphenyl or pyridyl. An embodiment of the present invention includescompounds wherein A² is phenyl. An embodiment of the present inventionincludes compounds wherein A² is naphthyl. An embodiment of the presentinvention includes compounds wherein A² is heteroaryl. An embodiment ofthe present invention includes compounds wherein A² is quinoxalinyl. Anembodiment of the present invention includes compounds wherein A² ispyridyl. An embodiment of the present invention includes compoundswherein A² is pyrazinly. An embodiment of the present invention includescompounds wherein A² is quinolinyl. An embodiment of the presentinvention includes compounds wherein A² is indolyl. An embodiment of thepresent invention includes compounds wherein A² is dihydroindolyl. Anembodiment of the present invention includes compounds wherein A² isbenzimidazolyl.

An embodiment of the present invention includes compounds wherein A³ ispyrazolyl. An embodiment of the present invention includes compoundswherein A³ is pyrazolyl which is substituted with methyl. An embodimentof the present invention includes compounds wherein A³ is pyridyl. Anembodiment of the present invention includes compounds wherein A³ ispyridyl, which is substituted with at least one substituent other thanhydrogen. An embodiment of the present invention includes compoundswherein A³ is pyridyl, which is substituted with fluororo or chloro. Anembodiment of the present invention includes compounds wherein A³ is2-pyridyl or 4-pyridyl. An embodiment of the present invention includescompounds wherein A³ is other than unsubstituted 3-pyridyl. Anembodiment of the present invention includes compounds wherein A³ isthiazolyl. An embodiment of the present invention includes compoundswherein A³ is 5-thiazolyl. An embodiment of the present inventionincludes compounds wherein A³ is thiazolyl, which is substituted withC₁₋₆alkyl. An embodiment of the present invention includes compoundswherein A³ is phenyl. An embodiment of the present invention includescompounds wherein A³ is phenyl, which is substituted with at least onesubstituent other than hydrogen. An embodiment of the present inventionincludes compounds wherein A³ is phenyl, which is substituted withhydroxyl, methylaminocarbonyl or dimethylaminomethyl. An embodiment ofthe present invention includes compounds wherein A³ is cyclopentyl. Anembodiment of the present invention includes compounds wherein A³ ismorpholinyl. An embodiment of the present invention includes compoundswherein A³ is pyrrolidinyl. An embodiment of the present inventionincludes compounds wherein A³ is azetidinyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b), and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl, and    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluororo, and    -   (4) methyl.

An embodiment of the present invention includes compounds wherein A¹ isphenyl and R^(1a), R^(1b) and R^(1c) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluororo, and    -   (4) methyl.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methoxy,    -   (6) t-butoxy,    -   (7) difluoromethyl, and    -   (8) trifluoromethyl,    -   (9) —N(CH₃).

An embodiment of the present invention includes compounds wherein A² isphenyl and R^(2a), R^(2b) and R^(2c) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methoxy,    -   (6) t-butoxy,    -   (7) difluoromethyl, and    -   (8) trifluoromethyl,    -   (9) —N(CH₃).

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl, and    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen, and    -   (3) C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluororo, and    -   (4) methyl.

An embodiment of the present invention includes compounds wherein A³ ispyridyl and wherein R^(3a) is halogen, R^(3b) is hydrogen and R^(3c) ishydrogen. An embodiment of the present invention includes compoundswherein A³ is pyridyl and wherein R^(3a) is chloro or fluoro, R^(3b) ishydrogen and R^(3c) is hydrogen.

An embodiment of the present invention includes compounds wherein A³ ispyrazolyl and wherein R^(3a) is C₁₋₆ alkyl, R^(3b) is hydrogen andR^(3c) is hydrogen. An embodiment of the present invention includescompounds wherein A³ is pyrazolyl and wherein R^(3a) is methyl, R^(3b)is hydrogen and R^(3c) is hydrogen.

An embodiment of the present invention includes compounds wherein R⁴ ishydrogen or C₁₋₆alkyl. An embodiment of the present invention includescompounds wherein R⁴ is hydrogen or methyl. An embodiment of the presentinvention includes compounds wherein R⁴ is hydrogen. An embodiment ofthe present invention includes compounds wherein R⁵ is hydrogen orC₁₋₆alkyl. An embodiment of the present invention includes compoundswherein R⁵ is hydrogen or methyl. An embodiment of the present inventionincludes compounds wherein R⁵ is hydrogen.

An embodiment of the present invention includes compounds wherein R⁶ ishydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl. An embodiment of the presentinvention includes compounds wherein R⁶ is C₁₋₆alkyl. An embodiment ofthe present invention includes compounds wherein R⁶ is C₃₋₆cycloalkyl.An embodiment of the present invention includes compounds wherein R⁶ ishydrogen, methyl or ethyl. An embodiment of the present inventionincludes compounds wherein R⁶ is hydrogen.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals can betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for antagonizing orexin receptor activity ortreating the disorders and diseases noted herein in humans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 μM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ulassay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 ul assay buffer. 30 ul of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 ul,incubated for 5 min and finally 25 ul of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

In particular, the compounds of the following examples had activity inantagonizing the rat orexin-1 receptor and/or the human orexin-2receptor in the aforementioned assays, generally with an IC₅₀ of lessthan about 50 μM. Many of compounds within the present invention hadactivity in antagonizing the rat orexin-1 receptor and/or the humanorexin-2 receptor in the aforementioned assays with an IC₅₀ of less thanabout 100 nM. Compounds of the present invention also have activity inthe radioligand binding assay, generally with a Ki<100 nM against theorexin-1 and/or the orexin-2 receptor. Additional data is provided inthe following Examples. Such a result is indicative of the intrinsicactivity of the compounds in use as antagonists of orexin-1 receptorand/or the orexin-2 receptor. In general, one of ordinary skill in theart would appreciate that a substance is considered to effectivelyantagonize the orexin receptor if it has an IC₅₀ of less than about 50μM, preferably less than about 100 nM. The present invention alsoincludes compounds within the generic scope of the invention whichpossess activity as agonists of the orexin-1 receptor and/or theorexin-2 receptor. With respect to other pyridyl compounds, the presentcompounds exhibit unexpected properties, such as with respect toincreased oral bioavailability, metabolic stability, decreasedinhibition of metabolic enzymes (such as decreased cytochrome P450 3A⁴(CYP3A⁴) inhibition), decreased inhibition of transporters (such asdecreased p-glycoprotein/PGP inhibition) and/or selectivity with respectto other receptors, including the human orexin-2 receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention have utility in treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with orexin receptors,including one or more of the following conditions or diseases: sleepdisorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the value which is calculated from the time thata subject sleeps divided by the time that a subject is attempting tosleep; improving sleep initiation; decreasing sleep latency or onset(the time it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing intermittent wakings during sleep; decreasingnocturnal arousals; decreasing the time spent awake following theinitial onset of sleep; increasing the total amount of sleep; reducingthe fragmentation of sleep; altering the timing, frequency or durationof REM sleep bouts; altering the timing, frequency or duration of slowwave (i.e. stages 3 or 4) sleep bouts; increasing the amount andpercentage of stage 2 sleep; promoting slow wave sleep; enhancingEEG-delta activity during sleep; decreasing nocturnal arousals,especially early morning awakenings; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disorders,overeating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g., children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; sexual dysfunction; psychosexual dysfunction; sexdisorder; adequacy of renal function; responsivity to anesthetics; mooddisorders, such as depression or more particularly depressive disorders,for example, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder and cyclothymic disorder, mood disordersdue to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumour/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociateive disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in specific embodiments the present invention provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordperession disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2λ/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: insulin sensitizers including (i) PPARγantagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor α agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fabric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081×,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,aminone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone 13 agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) a minorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPAagonists; PDE IV inhibitors; GABAA inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A²aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexyl, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as a minorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl;THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DIPEA:N,N-diisopropylethylamine; NMM: N-methylmorpholine; DMSO:dimethylsulfoxide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide;HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et₃N:triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovineserum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide;MTBE: methyl tert-butyl ether; SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidiniumhexafluorophosphate; rt: room temperature; HPLC: high performance liquidchromatography. The compounds of the present invention can be preparedin a variety of fashions. In some cases the final product may be furthermodified, for example, by manipulation of substituents. Thesemanipulations may include, but are not limited to, reduction, oxidation,alkylation, acylation, and hydrolysis reactions which are commonly knownto those skilled in the art. In some cases the order of carrying out theforegoing reaction schemes may be varied to facilitate the reaction orto avoid unwanted reaction products. The following examples are providedso that the invention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

Ethyl 2,5-dibromoisonicotinate (A-1) can be selectively reacted at the2-position under Suzuki reaction conditions to afford biarylintermediate A-2. A second Suzuki reaction on A-2 can afford triarylintermediates of type A-3. Triaryl esters of type A-3 can be saponifiedand then coupled to afford triarylisonicotinamides of type A-4.

Biaryl isonicotinates of type B-1 can be reacted under Pd-catalyzedamination conditions to afford intermediates of type B-2. Compounds suchas B-2 can be advanced to final compounds through saponification andamide coupling to afford B-3.

Example 1

ethyl 2,5-dibromoisonicotinate (1-2)

A solution of 2,5-dibromoisonicotinic acid (1-1, 5 g, 17.80 mmol) andsulfuric acid (1.23 mL, 23.1 mmol) in ethanol (100 mL) was heated toreflux overnight. After reducing the volume of ethanol by rotaryevaporation to approximately ¼ of it's original volume, the crudereaction mixture was partitioned between 2M sodium carbonate solutionand EtOAc, separating layers and washing the organic layer withsaturated sodium bicarbonate solution and brine. This solution was driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by normal phase column chromatography (0 to 50% EtOAc inhexanes) to afford the product (1-2) as a dark oil. ESI+MS[M]⁺C₈H₇Br₂NO₂=308.0.

ethyl 5-bromo-5′-methyl-2,3′-bipyridine-4-carboxylate (1-3)

To a solution ethyl 2,5-dibromoisonicotinate (1-2, 1.5 g, 4.86 mmol) indegassed dimethylformamide (24 mL) at 25° C. was added(5-methylpyridin-3-yl)boronic acid (0.665 g, 4.86 mmol), PdCl₂dppf(0.355 g, 0.486 mmol), cesium carbonate (4.75 g, 14.6 mmol) and water(0.262 mL, 14.57 mmol). The reaction flask was purged with nitrogen,sealed and stirred at 50° C. overnight. The crude reaction mixture waspartitioned between water and EtOAc, separating layers and washing theorganic layer with saturated sodium bicarbonate solution and brine. Thesolvent was removed by rotary evaporation and the crude product waspurified by normal phase column chromatography (0 to 50% EtOAc inhexanes) to afford the product (1-3) as a white solid.ESI+MS[M]⁺C₁₄H₁₃BrN₂O₂=321.0.

5′-methyl-5-phenyl-2,3′-bipyridine-4-carboxylic acid dihydrochloride(1-4)

To a solution ethyl 5-bromo-5′-methyl-2,3′-bipyridine-4-carboxylate(1-3, 0.3 g, 0.934 mmol) in degassed dimethylformamide (4 mL) at 25° C.was added phenylboronic acid (0.182 g, 1.5 mmol), PdCl₂dppf (0.068 g,0.093 mmol) and 4M aqueous cesium carbonate (0.817 mL, 3.27 mmol). Thereaction flask was purged with nitrogen, sealed and stirred for 2 hoursat 65° C., then overnight at room temperature. An additional 30 minutesof heating at 90° C. was required to drive the coupling to completion.After allowing the reaction to cool to room temperature, 1N LiOH (0.700mL) and water (1 mL) were added and the reaction was heated to 70° C.for 2 hours then stirred at room temperature overnight. The reactionmixture was concentrated to dryness by rotary evaporation. The crudeproduct was taken up in DMF/DMSO/CH₃CN/water (5 mL;2:2:1:0.5), filteredand purified by reverse phase preparative chromatography (5-40%acetonitrile in water with 0.1% TFA buffer). The clean fractions werepooled and evaporated to give the TFA salt as a white solid. Thismaterial was taken up in a minimal amount of THF/acetonitrile and ethylether saturated with HCl was added, forming a white precipitate. Thesolvent was decanted away after centrifugation of the suspension. Thiswas repeated 2 more times, once with HCl/ether and then with plain ethylether. After the final decant, the solids were dried under high vacuumto afford the title compound (1-4) as the Bis-HCl salt.ESI+MS[M+H]⁺C₁₈H₁₄N₂O₂.2HCl=291.1.

N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxamide(1-5)

To a solution of 5′-methyl-5-phenyl-2,3′-bipyridine-4-carboxylic aciddihydrochloride (1-4, 0.056 g, 0.153 mmol) in dimethylformamide (13 mL)cooled to 0° C., was added EDC (0.046 g, 0.24 mmol) and HOBt (0.039 g,0.257 mmol) followed by 1-(5,6-dimethoxypyridin-2-yl)methanamine (3-6,0.035 g, 0.206 mmol) and N-methylmorpholine (0.113 mL, 1.028 mmol). Thereaction was allowed to warm to room temperature and for 3 hours. Thereaction mixture was diluted with DMSO (1 mL), filtered and purified viareverse phase chromatography (5→65% acetonitrile in water with 0.1% TFAbuffer). The clean fractions were pooled, partitioned between ethylacetate and 2M sodium carbonate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound (1-5) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.76 (s, 1H) 8.52 (s, 1H), 8.21 (s,1H), 8.07 (s, 1H), 7.43 (m, 2H), 7.31 (t, J=6.59 Hz, 2H), 6.95 (d,J=8.05 Hz, 1H), 6.66 (d, J=7.81 Hz, 1H), 6.46 (m, 1H), 4.39 (d, J=5.37Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 2.44 (s, 3H). HRMS[M+H]C₂₆H₂₄N₄O₃calc'd 441.1921. found 441.1925.

TABLE 1 The following compounds were prepared using the methodologyherein, but substituting the appropriately substituted reagent, asdescribed in the Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation. Cmp Structure Name HRMS m/z (M + H) 1-6 

N-(3,4-dimethoxybenzyl)-2,5- bis(3,5-dimethyphenyl) isonicotinamide481.2483 found, 481.2486 required. 1-7 

N-(3,4-dimethoxybenzyl)-6- (3,5-dimethylphenyl)-3,3′-bipyridine-4-carboxamide 454.2121 found, 454.2125 required. 1-8 

N-(3,4-dimethoxybenzyl)-2- (3,5-dimethylphenyl)-5-(1-methyl-1H-pyrazol-4- yl)isonicotinamide 457.2246 found, 457.2234required. 1-9 

N-(3,4-dimethoxybenzyl)-5- methyl-3,2′:5′,3″-terpyridine- 4′-carboxamide441.1922 found, 441.1921 required. 1-10

6-(3-chloro-5-methylphenyl)- N-(3,4-dimethoxybenzyl)-3,3′-bipyridine-4-carboxamide 474.1575 found, 474.1579 required. 1-11

N-[(5,6-dimethoxypyridin-3- yl)methyl]-2-(3,5- dimethylphenyl)-5-phenylisonicotinamide 454.2121 found, 454.2125 required. 1-12

5″-chloro-N-[(5,6- dimethoxypyridin-2- yl)methyl]-2,3′:6′,3″-terpyridine-4′-carboxamide 462.1334 found, 462.1327 required. 1-13

N-[5,6-dimethoxypyrazin-2- yl)methyl]-5-(3-fluorophenyl)-5′-methyl-2,3′- bipyridine-4-carboxamide 460.1788 found,460.1779 required. 1-14

N-(3-cyclopropyl-4- methoxybenzyl)-5-(3- fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide 468.2088 found, 468.2082 required. 1-15

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5-(2-fluorophenyl)-5′-methyl-2,3′- bipyridine-4-carboxamide 459.1827 found,459.1827 required. 1-16

N-[(5,6-dimethoxypyridin-2- yl)methyl[-5-(3-fluorophenyl)-5′-methyl-2,3′- bipyridine-4-carboxamide 459.1831 found,459,1827 required. 1-17

5-(3-fluorophenyl)-N-[4- methoxy-3- (trifluoromethyl)benzyl]-5′-methyl-2,3′-bipyridine-4- carboxamide 496.1650 found, 496.1643 required.1-18

N-(3-chloro-4- methoxybenzyl)-5-(3- fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide 462.1385 found, 462.1379 required. 1-19

N-[(5,6-dimethoxypyridin-2- yl)methyl]-5′-methyl-5-pyrazin-2-yl-2,3′-bipyridine- 4-carboxamide 443.1829 found, 443.1826required.

Example 2

5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxylic acid (2-2)

To a solution of ethyl 5-bromo-5′-methyl-2,3′-bipyridine-4-carboxylate(2-1, 0.050 g, 0.156 mmol) in toluene (0.31 mL) at 25° C. was addedpyrrolidine (0.026 mL, 0.311 mmol), BINAP (0.0096 g, 0.016 mmol)followed by Pd(OAc)₂ (0.0035 g, 0.016 mmol) and cesium carbonate (0.076g, 0.234 mmol) and the system was heated in the microwave reactor at135° C. for 0.5 h. The system was partitioned between saturated aqueoussodium bicarbonate and EtOAc, washed with brine and dried over magnesiumsulfate. Filtration and concentration followed by purification vianormal phase chromatography (0→100% EtOAc in Hx) afforded a pale yellowoil. To this pale yellow oil (0.026 g, 0.083 mmol) in 1:1 THF/MeOH (0.40mL) at 25° C. was added aqueous sodium hydroxide (0.0125 mL, 0.125 mmol,10M) and the system was heated in the microwave reactor at 135° C. for10 minutes. The solvents were removed in vacuo to afford the titlecompound (2-2) as a grey solid. ESI+MS C₁₆H₁₇N₃O₂: 284.2 found, 284.1required.

N-[(5,6-dimethoxy-2-pyridinyl)methyl]-5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxamide(2-3)

To a solution of5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxylic acid (2-2,0.026 g, 0.085 mmol) and 1-(5,6-dimethoxy-2-pyridinyl)methanamine (3-6,0.017 g, 0.102 mmol) in DMF (0.17 mL) was added HATU (0.032 g, 0.085mmol) followed by DEA (0.074 mL, 0.426 mmol) and stirred at ambienttemperature for 1 h. The system was partitioned between saturatedaqueous sodium bicarbonate and EtOAc, washed with brine and dried overmagnesium sulfate. Filtration and concentration followed by purificationvia normal phase chromatography (0→10% MeOH in EtOAc) afforded the titlecompound (2-3) as a salmon powder. ¹H NMR (500 MHz, CDCl₃) δ 8.93 (s,1H), 8.40 (m, 1H), 8.32 (s, 1H), 8.06 (m, 1H), 7.08 (s, 1H), 7.06 (d,1H, J=8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 4.63 (d, 2H, J=4.5 Hz), 4.00 (s,3H), 3.89 (s, 3H), 3.36 (m, 4H), 2.40 (s, 3H), 1.93 (m, 4H).HRMS[M+H]C₂₄H₂₂N₅O₃ calc'd 434.2187. found 434.2211.

TABLE 2 The following coupounds were prepared using the methodologyherein, but substituting the appropriately substituted reagent, asdescribed in the Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation. Cmp Structure Name HRMS m/z (M + H) 2-4

5-azetidin-1-yl-N-[(5,6- dimethoxypyridin-2- yl)methyl]-5′-methyl-2,3′-bipyridine-4-carboxamide 420.2031 found, 420.2030 required.

Most of the benzylamines employed as starting materials herein werecommercially available. The following are examples of benzylaminesyntheses where the benzylamine was not commercially available. Theseexamples are illustrative only and should not be construed as limitingthe invention in any way.

Example 3

2-bromo-3-hydroxy-6-iodopyridine (3-2)

To a solution of 2-bromo-3-hydroxy pyridine (3-1, 28 g, 161 mmol) inwater (360 mL) was added K₂CO₃ (44.5 g, 322 mmol) and I₂ (40.8 g, 161mmol). The system was stirred for 1.5 h at ambient temperature, cooledto 0° C. and then treated with concentrated HCl until solidsprecipitated from solution (pH˜6.0). The solids were isolated byfiltration and dried to give the title compound (3-2) as a brown solid.ESI+MS C₅H₃BrINO: 299.8 found, 299.9 required.

2-bromo-3-methoxy-6-iodopyridine (3-3)

To a solution of 2-bromo-3-hydroxy-6-iodopyridine (3-2, 40 g, 133 mmol)in DMF (80 ml) was added K₂CO₃ (16.77 g, 121 mmol) and Methyl Iodide(29.2 mL, 467 mmol). The system was stirred for 45 minutes at 100° C.,cooled to room temperature and then treated with water (650 mL) andstirred for 0.5 h. The resulting solids that precipitated from solutionwere isolated by filtration and dried to give the title compound (3-3)as a pale brown solid. ESI+MS C₆H₅BrINO: 313.8 found, 313.9 required.

2,3-dimethoxy-6-iodopyridine (3-4)

To a solution of 2-bromo-3-methoxy-6-iodopyridine (3-3, 34 g, 108 mmol)in DMF (65 mL) was added sodium methoxide in methanol (37 mL, 162 mmol,4.37M) and heated to 100° C. The mixture was stirred for 10 minutes andpartitioned between saturated NaHCO₃ and DCM. The organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by gradient elution on silica (0 to 20%EtOAc in hexanes) to afford the title compound (3-4) as a white powder.ESI+MS[M+H]⁺C₇H₈INO₂: 265.8 found, 266.0 required.

2,3-dimethoxy-6-cyanopyridine (3-5)

To a solution of 2,3-dimethoxy-6-iodopyridine (3-4, 24.0 g, 91 mmol) inDMF (181 mL) was added copper cyanide (9.73 g, 109 mmol) and heated to150° C. for 20 minutes in a microwave reactor. The mixture waspartitioned between saturated sodium carbonate and EtOAc three times.The organic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by gradient elution onsilica gel (0 to 40% EtOAc in hexanes) to yield the desired product(3-5) as an off-white crystalline powder. ESI+MS[M+H]⁺C₈H₈N₂O₂: 165.0found, 165.1 required.

2,3-dimethoxy-6-aminomethylpyridine (3-6)

To a solution of 2,3-dimethoxy-6-cyanopyridine (3-5, 5.1 g, 31.1 mmol)in MeOH (260 mL) was added Pearlman's Catalyst (2.18 g, 3.11 mmol, 20 wt%) and concentrated HCl (20.0 mL, 249 mmol, 12M). The system was thenstirred under an atmosphere of hydrogen via a balloon for 1.5 h. Thereaction contents were filtered through a pad of celite and methanol wasremoved in vacuo. The crude mixture was then basified using saturatedNa₂CO₃ and then extracted using 4:1 Chloroform:Ethanol. The organicphase was washed with brine, dried over Na₂SO₄, filtered and purified bygradient elution on silica gel (0 to 12% MeOH(10% NH₄OH) in DCM) toyield the desired product (3-6) as a bone semi-solid.ESI+MS[M+H]⁺C₈H₁₂N₂O₂: M-16 (—NH₂), 152.06 found, 168.2 required.

Example 4

5-bromo-2,3-dimethoxypyridine (4-2)

To a solution of 2,3-dimethoxypyridine (4-1, 2.5 g, 18.0 mmol, 1.0equiv) in dichloromethane:saturated NaHCO₃ (80 mL: 40 mL) at 0° C. wasadded bromine (0.93 mL, 18.0 mmol, 1.0 equiv) and the reaction mixturewas stirred for 2 h at 25° C. The reaction mixture was quenched withsolid Na₂SO₃ (˜10 g) and the aqueous phase was extracted withdichloromethane (3×100 mL). The organic phase was dried over magnesiumsulfate and concentrated. The residue was purified via normal phasechromatography (0 to 20% EtOAc in hexanes, silica) to afford the desiredproduct (4-2) as an oil after concentration. ESI+MS[M+H]⁺C₇H₈NO₂ calc'd218.0. found 218.0.

5,6-dimethoxynicotinonitrile (4-3)

To a solution of 5-bromo-2,3-dimethoxypyridine (4-2, 0.300 g, 1.38 mmol,1.0 equiv) in dimethylformamide (3.9 mL) was added copper (I) cyanide(0.15 gL, 1.65 mmol, 1.2 equiv) and the reaction mixture was heated for40 minutes at 18° C. in a microwave reactor. The reaction mixture wascooled and partitioned between EtOAc (50 mL) and water (50 mL). Theorganic phase was washed with water (2×30 mL) and brine (1×30 mL), driedover magnesium sulfate and concentrated. The residue was purified vianormal phase chromatography (0 to 40% EtOAc in hexanes, silica) toafford the desired product (4-3) as white solid after concentration.ESI+MS[M+H]⁺C₈H₈N₂O₂ calc'd 165.1. found 165.1.

1-(5,6-dimethoxypyridin-3-yl)methanamine (4-4)

To a solution of 5,6-dimethoxynicotinonitrile (4-3, 0.600 g, 3.65 mmol,1.0 equiv) in methanol (20 mL) under a nitrogen atmosphere was addedPearlman's catalyst (0.205 g, 0.292 mmol, 0.08 equiv, 20 weight percent)and concentrated HCl (2.44 mL), and the reaction was place under anatmosphere of hydrogen. After 2 h, the reaction was placed under anatmosphere of nitrogen and filtered through celite to remove thecatalyst. The reaction mixture was dissolved in EtOAc, dried over MgSO₄and concentrated to an oily solid (4-4) of high purity.ESI+MS[M+H]⁺C₈H₁₂N₂O₂ calc'd 169.1. found 169.1.

Example 5

3-cyclopropyl-4-methoxybenzonitrile (5-2)

A mixture of 3-bromo-4-methoxybenzonitrile (5-1, 5.0 g, 23.6 mmol, 1.0eq), aqueous potassium phosphate tribasic (65.0 ml, 1.27 M, 3.5 eq),cyclopropylboronic acid (10.1 g, 118 mmol, 5.0 eq), Pd(OAc)₂ (0.539 g,2.36 mmol, 0.1 eq) and tricyclohexylphosphine (0.661 g, 2.36 mmol, 0.1eq) was stirred in degassed toluene (103 ml) and heated to 80° C. forthree hours. An additional amount of cyclopropylboronic acid (1.0 g,1.16 mmol, 0.5 eq) was added and the solution was further heated for 16hours at 80° C. to complete the reaction. The reaction mixture wascooled and partitioned between brine and EtOAc. The organic phase wasdried over sodium sulfate, filtered and concentrated to give an orangeoil. The oil was purified by normal phase column chromatography (0 to10% EtOAc in hexanes) to afford the product (5-2) as a yellow oil. ¹HNMR (CDCl₃) δ 7.44 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 6.86(d, 1H, J=8.4 Hz), 3.92 (s, 3H), 2.13 (m, 1H), 0.97 (m, 2H), 0.65 (m,2H).

1-(3-cyclopropyl-4-methoxyphenyl)methanamine (5-3)

Lithium aluminum hydride in diethyl ether (17.3 ml, 1.0 M, 17.3 mmol,3.0 eq) was carefully added over twenty minutes to a solution of3-cyclopropyl-4-methoxybenzonitrile (15-2, 1.0 g, 5.77 mmol, 1.0 eq) intetrahydrofuran (28.9 ml) at 0° C. under nitrogen atmosphere. Theresulting dark orange mixture was allowed to stir at 0° C. for 30 min,then carefully quenched in the following order: water (1.0 ml), 15% NaOHaqueous (1.0 ml) and water (3.0 ml). The resulting emulsion was stirredat room temperature for 30 min. Several spatula amounts of magnesiumsulfate was added to the mixture to remove any water. The entire mixturewas filtered through a pad of sodium sulfate, washing with ethylacetate. The collected filtrate was concentrated to give the product(5-3) as a yellow oil. ESI+MS[M−16]⁺C₁₁H₁₅NO: 161.1 found, 161.2required.

Example 6

2,3-dimethoxy-5-aminomethylpyrazine (6-2)

To a solution of 2,3-dichloropyrazine (6-1, 3.5 g, 23.5 mmol) in MeOH(115 mL) was added NaOMe (15.0 mL, 70.5 mmol) and the system was stirredovernight. The reaction contents were then filtered through a frittedfunnel of medium porosity, concentrated, and partitioned between EtOAcand water. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated to afford a clear oil. To this clear oil (2.5g, 17.8 mmol) in DMF (17 ml) at 0° C. was added NBS (3.5 g, 19.6 mmol)the system was stirred overnight. The system was quenched with Na₂SO₃and then poured into ice water. The resulting solids that precipitatedfrom solution were isolated by filtration and dried to afford a whitesolid. To this white solid (1 g, 4.5 mmol) in DMF (9 mL) was addedcopper cyanide (0.45 g, 5.0 mmol) and heated to 185° C. for 20 minutesin the microwave reactor. The mixture was cooled and partitioned betweenEtOAc and water. The organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude material was purified bygradient elution on silica (0 to 65% EtOAc in hexanes) to afford a whitepowder. To this white powder (0.740 g, 4.5 mmol) in MeOH (40 mL) wasadded Pearlman's Catalyst (0.315 g, 0.45 mmol) and concentrated HCl (3.0mL, 36 mmol). The system was then stirred under an atmosphere ofhydrogen via a balloon for 1.5 h. The reaction contents were filteredthrough a pad of celite followed by removal of methanol in vacuo. Thecrude mixture was then dissolved in DCM, basified using saturated Na₂CO₃and then extracted several times with DCM. The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated to yield thedesired product (6-2) as a bone solid. ESI+MS[M+H]⁺C₇H₁₁N₃O₂: M−16(—NH₂), 152.82 found, 169.2 required.

Example 7

Methyl 2-chloro-5-(1,3-thiazol-2-yl)isonicotinate (7-2)

To a 100 mL round bottom flask was addedbis(tri-tertbutylphosphine)palladium(0) (204 mg, 0.40 mmol, 0.1 equiv).The flask was then flushed with nitrogen and charged with 1,4-dioxane(20 mL), methyl 5-bromo-2-chloroisonicotinate (7-1, 1000 mg, 4.0 mmol, 1equiv) and 2-(tributylstannyl)-1,3-thiazole (1.5 mL, 4.8 mmol, 1.2equiv). The reaction mixture was heated for 3 hours at 65° C., dilutedwith EtOAc (20 mL) and filtered through celite. The filtrate wasconcentrated and the residue purified by normal phase columnchromatography (0-40% EtOAc in hexanes) to afford the title compound(7-2) as a yellow solid. ESI+MS[M+H]⁺C₁₀H₈ClN₂O₂S=255.0

Methyl 5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate(7-3)

Methyl 2-chloro-5-(1,3-thiazol-2-yl)isonicotinate (7-2, 6.5 g, 26 mmol,1 equiv), (5-methylpyridin-3-yl)boronic acid (3.8 g, 28 mmol, 1.1equiv), cesium carbonate (29 g, 89 mmol, 3.5 equiv) andPdCl₂(dppf)-CH₂Cl₂ adduct (4.2 g 5.1 mmol, 0.2 equiv) were suspended inDMF (102 mL) and water (4.6 mL, 255 mmol, 10 equiv). The reactionmixture was heated for 45 minutes at 65° C., diluted with EtOAc (200 mL)and filtered through celite. The organic layer was washed with water(2×200 mL), dried over MgSO₄ and concentrated. The residue was purifiedby normal phase column chromatography (40-80% EtOAc in hexanes) toafford the title compound (7-3) as a tan solid.ESI+MS[M+H]⁺C₁₆H₁₄N₃O₂S=312.1

Potassium 5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate(7-4)

To a solution of methyl5-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate (7-3, 890mg, 2.9 mmol, 1 equiv) in tetrahydrofuran (14.3 mL) was added potassiumtrimethylsilanolate (640 mg, 5.0 mmol, 1.75 equiv). The reaction mixturewas stirred at room temperature for 1 hour. Ethyl ether (15 mL) wasadded and the precipitate was filtered to afford the title compound(7-4) as a white solid. ESI+MS[M+H]⁺C₁₅H₁₂N₃O₂S=298.1

N-[(5,6-Dimethoxypyridin-2-yl)methyl]-5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide(7-5)

Potassium 5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate(7-4, 980 mg, 2.9 mmol, 1 equiv),1-(5,6-dimethoxypyridin-2-yl)methanamine (3-6, 490 mg, 2.9 mmol, 1equiv), EDC (670 mg, 3.5 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole(480 mg, 3.5 mmol, 1.2 equiv) and diisopropylethylamine (2.0 mL, 12mmol, 4 equiv) were suspended in DMF (14.6 mL) and the reaction mixturewas heated for 2 hours at 65° C. The reaction mixture was thenpartitioned between DCM (50 mL) and water (50 mL). The layers wereseparated and the organic layer was dried over MgSO₄ and concentrated.The residue was purified by normal phase column chromatography (0-20%MeOH in EtOAc) to afford a white solid that was recrystallized fromchloroform/hexanes to give the title compound (7-5) as a crystallinesolid (970 mg, 75% yield). ¹H NMR (CDCl₃, 300 MHz) δ 9.08 (s, 2H), 8.53(s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.81 (dd, J=3.1 and 1.1 Hz, 1H),7.78 (t, J=4.8 Hz, 1H), 7.43 (dd, J=3.3 and 1.1 Hz, 1H), 7.02 (d, J=7.9Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 4.58 (d, J=5.3 Hz, 2H), 3.91 (s, 3H),3.88 (s, 3H), 2.45 (s, 3H). HRMS (M+H)C₂₃H₂₁N₅O₃S calc'd 448.1438. found448.1443

TABLE 3 The following compounds were prepared using the foregoingmethodology, but substituting the appropriately substituted reagent, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis without undue experimentation. Cmp Structure Name NRMS m/z(M + H) 7-6

5′-chloro-N-[(5,6- dimethoxypyridin-2- yl)methyl]-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4- carboxamide 468.0912 found, 468.0892 required.7-7

N-[(5-cyclopropyl-6- methoxypyridin-2-yl)methyl]-5′-methyl-5-(1,3-thiazol-2-yl)- 2,3′-bipyridine-4-carboxamide 458.1638found, 458.1645 required. 7-8

N-(3-chloro-4- methoxybenzyl)-5′-methyl-5- (5-methyl-1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide 465.1139 found, 465.1147 required. 7-9

N-(3-ethyl-4-methoxybenzyl)- 5′-methyl-5-(4-methyl-1,3-thiazol-2-yl)-2,3′-bipyridine- 4-carboxamide 459.1841 found, 459.1849required.

Example 8

2-bromo-3-hydroxy-6-iodopyridine (8-2)

To a solution of 2-bromo-3-hydroxy pyridine (8-1, 28 g, 161 mmol) inwater (360 mL) was added K₂CO₃ (22.24 g, 161 mmol) and I₂ (20.42 g, 80mmol). The system was stirred for 1.5 h at ambient temperature, cooledto 0° C. and then treated with concentrated HCl until solidsprecipitated from solution (pH˜6.0). The solids were isolated byfiltration and dried to give the title compound (8-2) as a brown solid.ESI+MS[M+H]⁺C₅H₃BrINO=299.8

2-methoxy-3-hydroxy-6-cyanopyridine (8-3)

To a solution of 2-bromo-3-hydroxy-6-iodopyridine (8-2, 10 g, 33.3 mmol,1.0 equiv) in DMF (104 ml) was added TBAI (1.23 g, 3.33 mmol, 0.1equiv), diisopropylethylamine (17.5 mL, 100 mmol, 3.0 equiv) and SEM-Cl(8.87 mL, 50.0 mmol, 1.5 equiv). The system was stirred at ambienttemperature for 24 hours. The reaction was partitioned between EtOAc andsaturated NaHCO₃. The organic phase was washed with NaHCO₃ and driedover MgSO₄. After concentration, the residue was purified by normalphase column chromatography (0 to 50% EtOAc in hexanes) to afford a paleyellow oil. To this pale yellow oil in DMF (145 mL) was added a 4.37Msolution of NaOMe in MeOH(6.65 mL, 29.1 mmol, 1.0 equiv) and the systemwas heated to 100° C. for 1 hour. The system was cooled to ambienttemperature and partitioned between EtOAc and saturated NaHCO₃. Theorganic phase was washed with brine and dried over MgSO₄. Afterconcentration, the residue was purified by normal phase columnchromatography (0 to 20% EtOAc in hexanes) to afford a clear oil. Tothis clear oil in DMF (69 mL) was added CuCN (3.71 g, 41.4 mmol, 2.0equiv) and the system was irradiated at 160° C. for 0.5 hour. Thereaction mixture was filtered through celite and partitioned betweenEtOAc and brine. The organic phase was dried over MgSO₄ andconcentrated. The residue was purified by normal phase columnchromatography (0 to 50% EtOAc in hexanes) to afford a yellow solid.ESI+MS[M+H]⁺C₇H₆N₂O₂=151.0

1-(5-cyclopropyl-6-methoxypyridin-2-yl)methanamine (8-4)

To a solution of 2-methoxy-3-hydroxy-6-cyanopyridine (8-3, 0.82 g, 5.43mmol, 1.0 equiv) in THF (27 mL) at −78° C. was added a 2.0M solution ofNaHMDS in THF (4.07 mL, 8.14 mmol, 1.5 equiv) followed by Comins reagent(3.19 g, 8.14 mmol, 1.5 equiv) and the system was stirred at −78° C.until disappearance of starting material was observed via thin layerchromatography (1:1 EtOAc in hexanes used as solvent system for TLC).The system was then partitioned between EtOAc and brine and dried overMgSO₄. After concentration, the residue was purified by normal phasecolumn chromatography (0 to 50% EtOAc in hexanes) to afford a paleyellow oil. To this pale yellow oil in toluene (1.0 mL) and water (1.0mL) was added potassium cyclopropyltrifluoroborate salt (0.11 g, 0.744mmol, 1.05 equiv) followed by 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.03 eq, 0.021 mmol, 13.9 mg) and Cs₂CO₃ (0.690 g,2.13 mmol, 3.0 equiv) and the system was heated at 100° C. for 1.5hours. The system was then partitioned between EtOAc and brine and driedover MgSO₄. After concentration, the residue was purified by normalphase column chromatography (0 to 20% EtOAc in hexanes) to afford aclear oil. To this clear oil in MeOH (1.72 mL) was added Pearlman'sCatalyst (0.024 g, 0.03 mmol, 0.1 equiv) and concentrated HCl (0.23 mL,2.76 mmol, 8.0 equiv). The system was then stirred under an atmosphereof hydrogen via a balloon overnight. The reaction contents were filteredthrough a pad of celite and basified using saturated Na₂CO₃ Methanol wasthen removed in vacuo and the mixture was then extracted using 4:1Chloroform:Ethanol. The organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated to yield the desired product (84) as ayellow oil. ESI+MS[M+H]⁺C₁₀H₁₄N₂O=162.0 [M−16 (—NH₂)]

TABLE 4 The following table shows representative data for the compoundsof the Examples as orexin receptor antagonists as determined by theassays herein. OX2R K_(i) Cmpd Structure (nM) 1-5 

0.72 1-13

4.5  1-16

0.91 7-5 

0.95 7-7 

0.97

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: A¹ is selected from the group consisting of phenyl, naphthyland heteroaryl; A² is selected from the group consisting of phenyl,naphthyl and heteroaryl; A³ is selected from the group consisting ofphenyl, naphthyl, C₃₋₆cycloalkyl, —NR¹⁰R¹¹ and heterocycle; R^(1a),R^(1b) and R^(1c) may be absent if the valency of A¹ does not permitsuch substitution and are independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is independently 0 or 1, n isindependently 0 or 1 (wherein if m is 0 or n is 0, a bond is present)and where the alkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl,where the cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R¹³,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R¹³, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R¹³, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R¹³, (f)phenyl, which is unsubstituted or substituted with R¹³, and (g)heterocycle, which is unsubstituted or substituted with R¹³, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R^(2a), R^(2b) and R^(2c) may be absent if the valency ofA² does not permit such substitution and are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornaphthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(T)R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R^(3a), R^(3b) and R^(3c) may be absent if the valency of A³ does notpermit such substitution and are independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornaphthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl, whichis unsubstituted or substituted with one or more substituents selectedfrom R¹³, or R⁴ and R⁵ may be joined together to form a C₃₋₆cycloalkylwith the carbon atom to which they are attached, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR¹³; R⁶ is hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl, which is unsubstitutedor substituted with one or more substituents selected from R¹³; R¹³ isselected from the group consisting of: (1) halogen, (2) hydroxyl, (3)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (4)—O_(n)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (6) —(C═O)_(m)—C₂₋₄alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, wherethe heterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen,(3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heterocycle, (10)—CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 wherein A¹ is phenyl.
 3. The compound of claim 1wherein A¹ is pyridyl.
 4. The compound of claim 1 wherein A² is phenyl.5. The compound of claim 1 wherein A² is heteroaryl.
 6. The compound ofclaim 1 wherein A³ is phenyl.
 7. The compound of claim 1 wherein A³ isthiazolyl.
 8. The compound of claim 1 wherein R^(1a), R^(1b) and R^(1c)are independently selected from the group consisting of: (1) hydrogen,(2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl, phenyl or napthyl, (5) —O—C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is unsubstituted orsubstituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (7)phenyl, which is unsubstituted or substituted with halogen, hydroxyl,C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl, which is unsubstitutedor substituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,and (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂.
 9. The compound of claim 8 wherein R^(1a), R^(1b)and R^(1c) are independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl ornapthyl, and (5) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith halogen, hydroxyl or phenyl.
 10. The compound of claim 9 whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of: (1) hydrogen, (2) chloro, (3) fluororo, and (4) methyl.11. The compound of claim 1 wherein R^(2a), R^(2b) and R^(2c) areindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl or napthyl, (5)—O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl is selected frompyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl, which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and (9) —NH—C₁₋₆alkyl, or—N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted withhalogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 12. The compound ofclaim 11 wherein R^(2a), R^(2b) and R^(2c) are independently selectedfrom the group consisting of: (1) hydrogen, (2) chloro, (3) fluoro, (4)bromo, (5) methoxy, (6) t-butoxy, (7) difluoromethyl, and (8)trifluoromethyl, (9) —N(CH₃).
 13. The compound of claim 1 whereinR^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl,which is unsubstituted or substituted with halogen, hydroxyl, phenyl ornapthyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl isselected from pyrrolyl, imidazolyl, indolyl, pyridyl, and pyrimidinyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (7) phenyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and (9) —NH—C₁₋₆alkyl, or—N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstituted or substituted withhalogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.
 14. The compound ofclaim 13 wherein R^(3a), R^(3b) and R^(3c) are independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, and (3)C₁₋₆alkyl.
 15. A compound which is selected from the group consistingof:N-[(5,6-dimethoxypyridin-2-yl)methyl]-6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxamide;N-(3,4-dimethoxybenzyl)-2,5-bis(3,5-dimethylphenyl) isonicotinamide;N-(3,4-dimethoxybenzyl)-6-(3,5-dimethylphenyl)-3,3′-bipyridine-4-carboxamide;N-(3,4-dimethoxybenzyl)-2-(3,5-dimethylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isonicotinamide;N-(3,4-dimethoxybenzyl)-5-methyl-3,2′:5′,3″-terpyridine-4′-carboxamide;6-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)-3,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxypyridin-3-yl)methyl]-2-(3,5-dimethylphenyl)-5-phenylisonicotinamide;5″-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,3′:6′,3″-terpyridine-4′-carboxamide;N-[(5,6-dimethoxypyrazin-2-yl)methyl]-5-(3-fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide;N-(3-cyclopropyl-4-methoxybenzyl)-5-(3-fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5-(2-fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5-(3-fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide;5-(3-fluorophenyl)-N-[4-methoxy-3-(trifluoromethyl)benzyl]-5′-methyl-2,3′-bipyridine-4-carboxamide;N-(3-chloro-4-methoxybenzyl)-5-(3-fluorophenyl)-5′-methyl-2,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-5-pyrazin-2-yl-2,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxy-2-pyridinyl)methyl]-5′-methyl-5-(1-pyrrolidinyl)-2,3′-bipyridine-4-carboxamide;5-azetidin-1-yl-N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-2,3′-bipyridine-4-carboxamide;N-[(5,6-dimethoxypyridin-2-yl)methyl]-5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide;5′-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide;N-[(5-cyclopropyl-6-methoxypyridin-2-yl)methyl]-5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide;N-(3-chloro-4-methoxybenzyl)-5′-methyl-5-(5-methyl-1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide;N-(3-ethyl-4-methoxybenzyl)-5′-methyl-5-(4-methyl-1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 17. (canceled) 18.(canceled)
 19. A method for enhancing the quality of sleep in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 1 ora pharmaceutically acceptable salt thereof.
 20. A method for treatinginsomnia in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 21. Amethod for treating or controlling obesity in a mammalian patient inneed thereof which comprises administering to the patient atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.